CLINICAL PHARMACOLOGY

Cytochrome P450: New Nomenclature

and Clinical Implications
MELANIE JOHNS CUPP, PHARM.D., and TIMOTHY S. TRACY, PH.D.
West Virginia University School of Pharmacy, Morgantown, West Virginia

Many drug interactions are a result of inhibition or induction of cytochrome P450

enzymes (CYP450). The CYP3A subfamily is involved in many clinically significant ,
drug interactions, including those involving nonsedating antihistamines and cisapride,
that may result in cardiac dysrhythmias. CYP3A4 and CYP1A2 enzymes are involved
in drug interactions involving theophyUine. CYP2D6 is responsible for the metabolism
of many psychotherapeutic agents. The protease inhibitors, which are used to treat
patients infected with the human immunodeficiency virus, are metabolized by the
CYP450 enzymes and consequently interact with a multitude of other medications. By
understanding the unique functions and characteristics of these enzymes, physicians
may better anticipate and manage drug interactions and may predict or explain an
individual's response to a particular therapeutic regimen.

T
Richard W. Sloan, he basic purpose of drug metab- involves competition with another drug for
M.D., R.PH., olism in the body is to make the enzyme binding site. This process usually
coordinator of this
series, is chairman
drugs more water soluble and begins with the first dose of the inhibitor,*'
and residency thus more readily excreted in and onset and offset of inhibition correlate
program director the urine or bile.'-^ One com- with the half-lives of the drugs involved.'
of the Department of mon way of metabolizing drugs involves the Enzyme induction occurs when a drug
Family Medicine
alteration of functional groups on the parent stimulates the synthesis of more enzyme pro-
at York (Pa.)
Hospital and clinical molecule (e.g., oxidation) via the cytochrome tein,' enhancing the enzyme's metabolizing
associate professor in P450 enzymes. These enzymes are most pre- capacity. It is somewhat difficult to predict the
family and community dominant in the liver but can also be found in time course of enzyme induction because sev-
medicine at the Milton the intestines, lungs and other organs.'* eral factors, including drug half-lives and
S. Hershey Medical
Center, Pennsylvania
These cytochrome P450 enzymes are desig- enzyme turnover, determine the time course
State University, Her- nated by the letters "CYP" followed by an Ara- of induction.
shey, Pa. bic numeral, a letter and another Arabic
numeral (e.g., CYP2D6).^ Each enzyme isIllustrative Case 1
termed an isoform since each derives from a
A 74-year-old woman with insulin-depen-
different gene. It should be noted, however,
dent (type 2) diabetes had been taking meto-
that structural similarity of enzymes cannot
prolol and warfarin for atrial fibrillation and
be used to predict which isoforms will be
amitriptyline, 50 mg at bedtime, for diabetic
responsible for a drug's metabolism. neuropathy, for several years. On the death of
Drug interactions involving the cyto-
her husband, she presented with symptoms of
chrome P450 isoforms generally result from
depression, and paroxetine was added to her
one of two processes, enzyme inhibition or
medication regimen with the rationale that
enzyme induction. Enzyme inhibition usually
paroxetine would cause fewer side effects than
an increase in the amitriptyline dosage. Three
days after the initiation of paroxetine therapy,
Until genetic tests for isoform expression become available, a the woman was brought to the emergency
department by her daughter, who had found
physidm can often antidpBte drug interactions in a patient by
her asleep at 11 a.m. On awakening, the
. knowing-i^c-hniedications inhibitor induce P450 enzymes. patient complained of dry mouth and dizzi-
ness. The emergency department physician,

JANUARY 1,1998 / VOLUME 57, NUMBER 1 AMERICAN FAMILY PHYSICIAN 107

Cytochrome P450
die anadepres-
ing deoendi, on
conccimitdnt medicst'oos.
noting that paroxetine had recently been
added to the medication regimen, changed
the patient to fiuoxetine, which he thought
would be less sedating. Three days later, the
patient was still very sedated and dizzy, and
complained of difficulty urinating. She was
again brought to the emergency department,
where bladder catheterization yielded two
liters of dark urine. Her International Norma-
lized Ratio (INR) was 4.0.
On discussion with a colleague, the emer-
gency department physician learned that both
paroxetine and fiuoxetine can inhibit cyto-
chrome P450 enzymes (isoforms) responsible
for the metabolism of the patient's other
medications. This example illustrates the need
to understand the cytochrome P450 isoforms
responsible for drug metabolism and their
inhibitors and inducers.
Cytochrome P450 Isoforms
CYP2D6
CYP2D6 has been studied extensively
because it exhibits genetic polymorphism,
meaning that distinct population differences
are apparent in its expression or activity.
Approximately 7 to 10 percent of Caucasians
are poor metabolizers of drugs metabolized by
CYP2D6."' Individuals with normal CYP2D6
activity are termed extensive metabolizers.
Ethnic differences are indicated in this genetic
polymorphism, since Asians and blacks are
less likely than Caucasians to be poor metabo-
lizers."''^ Poor metabolizers are at risk for
drug accumulation and toxicity fi-om drugs
metabolized by this isoform. For example, one
patient who suffered cardiotoxicity induced by
desipramine (Norpramin) was found to be a
poor metabolizer." Poor metabolizers of
CYP2D6 substrates are at risk for postural
hypotension and antipsychotic side effects
108 AMERICAN FAMILY PHYSICIAN
such as oversedation, because several antipsy-
chotic agents are metabolized by CYP2D6.'''
In a study of 45 elderly patients (five of whom
were poor metabolizers) receiving per-
phenazine, side effects increasedfivefoldin the
poor metabolizers compared with the exten-
sive metabolizers.'^ Conversely, when forma-
tion of an active metabolite is essential for
drug action, poor metabolizers of CYP2D6
can exhibit less response to drug therapy com-
pared with extensive metabolizers. Codeine is
0-demethylated to morphine by CYP2D6,
which accounts at least partially for its anal-
gesic effect."^ Thus, poor metabolizers may
have less response to codeine than other per-
sons. The substrates and inhibitors of
CYP2D6 are listed in Table 1.
Psychotherapeutic Agents. Many antidepres-
sants are metabolized by CYP2D6, but other
cytochrome P450 isoforms can also contribute
to their metabolism (Tables 1 through 6). The
clinical importance of this "dual metabolism"
will be illustrated later. With respect to drugs
inhibiting CYP2D6, cimetidine (Tagamet), the
selective serotonin reuptake inhibitors (SSRIs)
and some tricyclic antidepressants function as
inhibitors of this P450 isoform."-" Of the
antidepressants, paroxetine (Paxil) appears to
have the greatest ability to inhibit the metabo-
lism of CYP2D6 substrates. This is followed by
fiuoxetine (Prozac) and norfluoxetine; sertra-
line (Zoloft) and desmethylsertraline; fiuvox-
amine (Luvox), nefazodone (Serzone) and
venlafaxine (Effexor); clomipramine (Anaira-
nil), and amitriptyline (Elavil)." This ranking
is based on in vitro data, however, and the
choice of an antidepressant should be based
on factors other than the propensity to inhibit
CYP2D6. Although sertraline appears to be
less likely than the other SSRIs to inhibit
CYP2D6, inhibition may still occur at doses
greater than 50 mg. The clinical significance of
the inhibition of tricyclics by SSRIs or cimeti-
dine is subject to variation in enzyme activity
between individuals, the degree to which the
patient metabolizes and co-ingestion of other
enzyme inhibitors.^"
VOLUME 57, NUMBER 1 / JANUARY 1, 1998
 may occur in patients taking higher dosages of
CYP3A fluconazole or in patients with risk factors for
Inhibitors ofCYP3A. Members of the CYP3A ventricular arrhythmia. These two drugs
subfamily are the most abundant cytochrome should be used together with caution.
enzymes in humans. They account for 30 per- In addition to the azole antifungal med-
cent of the cytochrome P450 enzymes in the ications, the macrolide antibiotics can also
liver^' and are also substantially expressed in inhibit terfenadine metabolism, resulting in
the intestines. Members of this subfamily are the development of torsade de pointes.
involved in many clinically important drug Erythromycin and clarithromycin (Biaxin)
interactions.' Substrates, inhibitors and induc- have been shown to alter terfenadine
ers of CYP3A are listed in Table 2. metabolism, but this does not appear to
Nonsedating Antihistamines. High plasma occur with azithromycin (Zithromax).^'
concentrations of terfenadine (Seldane) and Thus, a patient who is taking terfenadine
astemizole (Hismanal) have been associated and needs macrolide antibiotic therapy
with torsade de pointes, a life-threatening car- should be given azithromycin to avoid pos-
diac arrhythmia characterized by altered car- sible cardiac consequences.
diac repolarization and a prolonged QT inter-
val.^^ Terfenadine is a prodrug that undergoes
complete first-pass metabolism to an active TABLE 1
carboxymetabolite.^' It is therefore unusual to Substrates and Inhibitors of CYP2D6
detect terfenadine in the plasma of patients
Substrates Inhibitors
who take this drug at the recommended Antidepressants* Antidepressants
dosage. Since it is terfenadine rather than its Amitriptyline (Elavil) Paroxetine > fluoxetine >
active metabolite that is cardiotoxic, arrhyth- Clomipramine (Anafranil) sertraline (Zoloft) > fluvoxamine
mias occur when a build-up of parent terfen- Desipramine (Norpramin) (Luvox),
adine takes place. This may occur when azole Doxepin (Adapin, Sinequan) Nefazodone (Serzone),
antifungal medications or macrolide antibi- Fluoxetine (Prozac) Venlafaxine > clomipramine
(Anafranil) > amitriptyline
otics are taken concomitantly.^^'^'' To counter- Imipramine (Tofranil)
Nortriptyline (Pamelor) Cimetidine (Tagamet)
act this problem, fexoferiadine (Allegra), the
Paroxetine (Paxil) Eluphenazine (Prolixin)
active metabolite of terfenadine, is now mar- Antipsychotics
Venlafaxine (Effexor)
keted as a noncardiotoxic alternative to terfe- Haloperidol
Antipsychotics
nadine. Like fexofenadine, loratadine (Clari- Perphenazine
Haloperidol (Haldol)
tin) does not appear to be cardiotoxic and Perphenazine (Etrafon, Trilafon)
Thioridazine
thus is also a safe nonsedating antihistamine Risperidone (Risperdal)
alternative.^^ Thioridazine (Mellaril)
Ketoconazole (Nizoral), itraconazoie (Spo- Beta blockers
ranox) and fluconazole (Diflucan) inhibit Metoprolol (Lopressor)
CYP3A, although ketoconazole and itracona- Penbutolol (Levatol)
Propranolol (Inderal)*
zoie are more inhibiting than fluconazole.^*
Timolol (Blocadren)
Based on in vitro and in vivo studies, keto-
Narcotics
conazole and itraconazoie markedly inhibit Codeine, tramadol (Ultram)
metabolism of terfenadine, causing changes
in the QT interval."" At dosages of 200 mg *—Other enzymes are also involved.
daily, fluconazole did not result in accumula-
NOTE: Inhibitors will decrease metabolism of substrates and generally lead to
tion of parent terfenadine or changes ih the increased drug effect (unless the substrate is a prodrug). inducers will increase
QT interval.^" However, an interaction with metabolism of substrates and generally lead to decreased drug effect (unless
terfenadine and fluconazole coadministration the substrate is a prodrug).

JANUARY 1,1998 / VOLUME 57, NUMBER 1 AMERICAN FAMILY PHYSICIAN 109

 Cytochrome P450

The SSRIs are 28 to 775 times less potent as
inhibitors of terfenadine metabolism than
ketoconazole.^° With respect to ability to
inhibit CYP3A, the following order of the
SSRIs is observed: nefazodone is greater than
fluvoxamine, and norfluoxetine is greater than
fluoxetine, which is greater than sertraline,
desmethylsertraline, paroxetine and venlafax-
ine.^' Several clinically important cardiac
events have been reported in patients receiving
fluoxetine or fluvoxamine with terfenadine or
astemizole.^"'^^'^^ The use of fluvoxamine or
nefazodone with terfenadine or astemizole is
contraindicated, and the U.S. Food and Drug
Administration is currently considering requir-
ing a contraindication against the use of other
SSRIs with the nonsedating antihistamines.'"
The package insert for sertraline contains a
warning against its use with terfenadine and
astemizole.'"* In patients who need to take an

TABLE 2
Substrates, Inhibitors and tnduoers of CYP3A
Substrates Inhibitors
Amitriptyline* (Elavil) Anfidepressants
Benzodiazepines Nefazodone > fluvoxamine (Luvox) > fluoxetine
Alprazolam (Xanax) (Prozac) > sertraline
Triazolam (Halcion) Paroxetine (Paxil)
Midazolam (Versed) Venlafaxine.
Calcium blockers Azole antifungals
Carbamazepine (Tegretol) Ketoconazole (Nizoral) > itraconazoie (Sporanox)
Cisapride (Propulsid) > fluconazole (Diflucan)
Dexamethasone (Decadron) Cimetidine (Tagamet)t
Erythromycin Clarithromycin (Biaxin) ,
Ethinyl estradiol (Estraderm, Estrace) Diltiazem
Glyburide (Glynase, Micronase) Erythromycin
Imipramine* (Tofranil) Protease inhibitors
Ketoconazole (Nizoral) Inducers
Lovastatin (Mevacor) Carbamazepine
Nefazodone (Serzone) Dexamethasone
Terfenadine (Seldane) Phenobarbital
Astemizole (Hismanal) Phenytoin (Dilantin)
Verapamil (Calan, Isoptin) Rifampin (Rifadin, Rimactane)
Sertraline (Zoloff)
Testosterone
Theophylline* '
Venlafaxine (Effexor)
Protease inhibitors

Ritonavir (Norvir)
Saquinavir (Invirase)
Indinavir (Crixivan)
Nelfinavir (Viracept)

*—Other enzymes are involved.

t—Does not inhibit ail CYP3A substrates: does not inhibit terfenadine metabolism.

NOTE: Inhibitors vi/ill decrease metabolism of substrates and generally lead to increased drug effect (unless
the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased
drug effect (unless the substrate is a prodrug).

110 AMERICAN FAMILY PHYSICIAN VOLUME 57, NUMBER 1 / JANUARY 1,1998

antidepressant and a nonsedating antihista-
mine concurrently, paroxetine, venlafaxine and Erythromycin, clarithromycin and ketoconazole inhibit
tricyclic antidepressants may be safe options, CYP3A, causing build-up of drugs metabolized by the same
since they inhibit CYP3A m.ore weakly.^^'^*^ enzyme. Terfenadine and cisapride are examples of drugs
Conversely, fexofenadine or loratadine, neither
that can rise to cardiotoxic levels.
of which are associated with arrhythmias,
could be prescribed, thus permitting more
freedom in the choice of an antidepressant.'
Cisapride. Serious ventricular arrhythmias itraconazole, metronidazole, erythromycin
have been reported in patients taking cis- and clarithromycin have been associated with
apride (Propulsid) and drugs that inhibit cisapride-induced torsade de pointes.^^ Con-
CYP3A, the isoform responsible for metabo- current use of cisapride with fluoxetine, ser-
lism of cisapride.^^ Ketoconazole, fluconazole. traline, fluvoxamine and nefazodone might be
problematic because of CYP3A inhibition.^"
Theophylline. Erythromycin'^ and clarith-
TABLE 3 romycin*" (but not azithromycin'") decrease
Substrates, Inhibitors theophylline metabolism by inhibiting CYP3 A.
and Inducers of CYIP1A2 The interaction between erythromycin and
_ J theophylline is most likely to occur in patients
Substrates
receiving higher dosages of erythromycin and
Amitriptyline* (Elavil)
Clomipramine (Ahafranil)*-
increases with the duration of therapy.
Clozapine (Clozaril)* . Inducers of CYP3A. Because of the resur-
Imipramine (Tofranil)* gence of tuberculosis in the United States,
Propranolol (Inderal)* rifampin (Rifadin, Rimactane), an inducer of
R-warfarin* the CYP3A subfamily, is being prescribed more
Theophyiline* widely than in previous years. Of particular
Tacrine (Cognex) clinical relevance is the potential reduction of
Inhibitors oral contraceptive efficacy by rifampin, since
Fluvoxamine (Luvox) estradiol levels can be reduced by rifampin-
Grapefruit juice mediated CYP3A induction.''^ In addition to
Quinolones rifampin, potent glucocorticoids such as dex-
Ciprofloxacin (Cipro)
amethasone (Decadron) are also inducers of
Enoxacin (Penetrex) > norfloxacin (Noroxin) >
CYP3A, but lower-potency glucocorticoids,
ofloxacin (Floxin) > lomefloxacin (Maxaquin)
such as prednisolone, have minimal effect.''^
Inducers
Omeprazole (Prilosec) CYP1A2
Phenobarbital •
Phenytoin-(Dilantin)
CYP1A2 can be induced by exposure to
Rifampin (Rifadin, Rimactane)
polycyclic aromatic hydrocarbons, such as
Smoking those found in charbroiled foods and cigarette
Charcoal-broiled meat* smoke.'*'' This is the only P450 isoform affect-
ed by tobacco. Cigarette smoking can result in
*—Other enzymes involved. an increase of as much as threefold in CYP1A2
NOTE: Inhibitors will decrease metabolism of sub- activity.'*'' Theophylline is metabolized in part
strates and generally lead to increased drug effect by CYP1A2,'*^ which explains why smokers
(unless the substrate is a prodrug). Inducers wiil require higher doses of theophylline than non-
increase metabolism of substrates and generally
lead to decreased drug effect (unless the substrate smokers. Table 3 lists the substrates, inhibitors
is a prodrug). and inducers of CYP 1A2.

JANUARY 1,1998 / VOLUME 57, NUMBER 1 AMERICAN FAMILY PHYSICIAN 111

Cytochrome P450
Quinolones. Certain quinolone antibiotics
can inhibit theophylline metabolism,'*'^'*''
although this effect is highly variable. The
interaction between enoxacin (Penetrex) or
ciprofloxacin (Cipro) and theophylline'*^ is
most significant in patients with plasma the-
ophylline concentrations at the upper end of
normal. Conversely, norfloxacin (Noroxin)
and ofloxacin (Floxin) have little effect on
theophylline concentrations,'*'' and lome-
floxacin (Maxaquin) does not appear to alter
the pharmacokinetics of theophylline.'*' Since
cimetidine is an inhibitor of CYP1A2,'^ addi-
tive inhibition of theophylline metabolism
occurs when cimetidine is combined with a
fluoroquinolone.
CYP2E1
This isoform is inducible by ethanol and
isoniazid and is responsible in part for the
metabolism of acetaminophen.^" The prod-
uct of acetaminophen's cytochrome P450
metabolism is a highly reactive intermediate
that must be detoxified by conjugation with
glutathione.^' Patients with alcohol depen-
dence may be at increased risk for aceta-
minophen hepatotoxicity because ethanol
induction of CYP2E1 increases formation of
this reactive intermediate, and glutathione
concentrations are decreased in these
patients.^^ Cimetidine exhibits only moder-
The Authors
MELANIE JOHNS CUPP, PHARM.D., is a clinical assistant professor at West Virginia Uni-
versity School of Pharmacy and a drug information specialist at West Virginia Drug
Information Center, both in Morgantown. She earned her pharmacy degree at West
Virginia University School of Pharmacy and completed a hospital pharmacy practice
residency at West Virginia University Hospitals.
TIMOTHY S. TRACY, PH.D., is an assistant professor of clinical pharmacology in the
Department of Basic Pharmaceutical Sciences at the West Virginia University School of
Pharmacy. He earned a Ph.D. in pharmacy from Purdue University, Lafayette, Ind., and
completed a postdoctoral fellowship in clinical pharmacology at the Indiana Universi-
ty School of Medicine, indianapolis.
Address correspondence to Melanie Johns Cupp, Pharm.D., West Virginia University
School of Pharmacy 1124 HSN, P.O. Box 9550, Morgantown, VW 26506-9550.
Reprints are not available from the authors.
112 AMERICAN FAMILY PHYSICIAN
TABLE 4
Substrates, Inhibitors
and Inducers of CYP2E1
Substrates
Acetaminophen (Tylenol)
Efhanol
Inhibitors
Disulfiram (Antabuse)
Inducers
Ethanol
Isoniazid (Laniazid)
NOTE: inhibitors will decrease metabolism of sub-
strates and generally iead to increased drug effect
(uniess the substrate is a prodrug). inducers wiil
increase metaboiism of substrates and generaily
lead to decreased drug effect (unless the substrate
is a prodrug).
ate affinity for this isoform and produces no
significant inhibition of the production of
acetaminophen's toxic metabolite.'^ Table 4
lists the substrates, inhibitors and inducers of
CYP2E1.
CYP2C9
S-Warfarin. Warfarin is produced as a
racemic mixture of R-warfarin and S-war-
farin, but the predominance of pharmacolog-
ic activity resides in the S-enantiomer.^^ Most
metabolism of S-warfarin is by means of
CYP2C9,^'* and inhibition of this isoform
results in several clinically important drug
interactions. Fluconazole, metronidazole,
micqnazole and amiodarone are a few exam-
ples of the many drugs that profoundly inhib-
it S-warfarin metabolism and produce
marked increases in prothrombin time mea-
surements.^^•^'' Interestingly, cimetidine, a
very weak inhibitor of CYP2C9,'^ has been
shown to have very little effect on warfarin
concentrations.^' The substrates, inhibitors
and inducers of CYP2C9 are listed in Table 5.
Phenytoin. Phenytoin is primarily metabo-
lized via CYP2C9,^'' although CYP2C19 may
also play a small role.'"' As stated above, cime-
tidine is a weak inhibitor of CYP2C9. It is
VOLUME 57, NUMBER 1 / JANUARY 1,1998
most likely to cause clinically significant inhi-
TABLE 5
bition of phenytoin metabolism at cimetidine
Substrates, Inhibitors
dosages greater than 1,200 mg in patients at
and Inducers of CYP2C9
the upper end of the phienytoin therapeutic
range.*^^ In patients with nonlinear metabo- Substrates
lism of phenytoin at relatively low serum lev- Nonsteroidal anti-inflammatory drugs
els, the risk of interaction with cimetidine is Phenytoin (Dilantin)
increased. However, it is difficult to identify S-warfarin
these patients in a clinical situation. Torsemide (Demadex)

Inhibitors
CYP2C19 Fluconazole (Diflucan)
Like CYP2D6, CYP2C19 has been shown to Ketoconazole (Nizoral)
exhibit genetic polymorphism.'^-''''' This en- Metronidazole (Flagyl)
Itraconazole (Sporanox)
zyme is completely absent in 3 percent of
Ritonavir (Norvir)
Caucasians and 20 percent of Japanese. Drugs
metabolized by this isoform include omepra- Inducers

zole (Prilosec),''^ lansoprazole (Prevacid)'''' Rifampin (Rifadin, Rimactane)

and diazepam (Valium),,'^'' However, clinical

examples of excessive or adverse drug effects
in people who are CYP2C19-deficient are
lacking. Table 6 lists the substrates and
inhibitors of CYP2C19.
NOTE: Inhibitors will decrease metabolism of sub-
strates and generally lead to increased drug effect
(unless the substrate is a prodrug). Inducers will
increase metabolism of substrates and generally
lead to decreased drug effect (unless the substrate
is a prodrug).

Illustrative Case 2
A 47-year-old man recently diagnosed with
HIV infection visited his physician with flush-
ing, dizziness and swelling of the feet and TABLE 6
ankles. He had been taking sustained-release Substrates and Inhibitors
nifedipine for treatment of hypertension for of CYP2C19
about three years. Approximately two weeks
Substrates
earlier, his physician had prescribed a combi-
Clomipramine (Anafranil)*
nation of lamivudine, zidovudine and the
Diazepam (Vaiium)*
protease inhibitor ritonavir. Imipramine (Tofranil)*
The HIV-1 protease inhibitors ritonavir, Omeprazole (Priiosec)
indinavir, saquinavir and nelfinavir all inhibit Propranoioi (Inderal)*
the CYP3A subfamily of enzymes, thus Inhibitors
increasing the serum levels of other drugs that Fiuoxetine (Prozac)
are metabolized by this pathway, including Sertraline (Zoloft)
nifedipine. It is likely that the addition of Omeprazole
ritonavir to this patient's medical regimen Ritonavir (Norvir)
resulted in an increase in the serum level of
nifedipine and the subsequent symptoms of *—Other enzymes involved also.
flushing and dizziness. Of the currently avail- NOTE: Inhibitors will decrease metabolism of sub-
able protease inhibitors, ritonavir, because of strates and generally lead to increased drug effect
(unless the substrate is a prodrug). Inducers will
its ability to both inhibit and induce CYP450
increase metabolism of substrates and generally
enzymes, is associated v/ith the most drug- lead to decreased drug effect (unless the substrate
drug interactions.'^*' is a prodrug).

JANUARY 1,1998 / VOLUME 57, NUMBER 1 AMERICAN FAMILY PHYSICIAN 113

Cytochrome P450
Final Comment
Physicians who become familiar with the
role of the various cytochrome P450 enzymes
in drug metabolism can often predict the con-
sequences of drug interactions and explain
patients' responses to medication regimens.
Although tests for isoform expression are not
widely available, it is conceivable that such
testing may become standard practice in the
future, given the clinical importance of iso-
form deficiencies. In the future, testing may
help to identify individuals at risk for drug
interactions and adverse events.
REFERENCES
1. Slaughter RL, Edwards DJ. Recent advances: the
cytochrome P450 enzymes. Ann Pharmacother
1995:29:619-24.
2. Gram TE. Metabolism of drugs. In: Craig CR, Stitzel
RE, eds. Modern pharmacology 4th ed. Boston: Lit-
tle, Brown, 1994:33-46.
3. Guengerich FP. Catalytic selectivity of. human
cytochrome P450 enzymes: relevance to drug meta-
bolism and toxicity Toxicol Lett 1994;70:133-8.
4. Kolars JC, Lovs/n KS, Schmiedlin-Ren P, Ghosh M,
Fang C, Wrighton SA, et al. CYP3A gene expres-
sion in human gut epithelium. Pharmacogenetics
1994:4:247-59.
5. Wheeler CW, Guenthner TM. Spectroscopic quan-
titation of cytochrome P-450 in human lung micro-
somes. J Biochem Toxicol 1990:5:269-72.
6. Philpot RM. Characterization of cytochrome P450
in extrahepatic tissues. Meth Enzymology 1991;
206:623-31.
7. Nelson DR, Kamataki T, Waxman DJ, Guengerich
FP, Estabrook RW, Feyereisen R, et al. The P450
superfamily: update on new sequences, gene map-
ping, .accession numbers, early trivial names of
enzymes, and nomenclature. DNA Cell Biol
1993;12:1-51.
8. Murray M, Reidy GF Selectivity in the inhibition of
mammalian cytochromes P-450 by chemical
agents. Pharmacol Rev 1990:42:85-101.
9. Dossing M, Pilsgaard H, Rasmussen B, Poulsen HE.
Time course of phenobarbital and cimetidine medi-
ated changes in hepatic drug metabolism. Eur J
Clin Pharmacol 1983:25:215-22.
10. Steiner E, Bertilsson L, Sawe J, Bertling I, Sjoqvist F
Polymorphic debrisoquin hydroxylation in 757
Swedish subjects.' Clin Pharmacol Ther 1988:
44:431-5.
11. Relling MV, Cherrie J, Schell MJ, Petros WP, Meyer
WH, Evans WE. Lower prevalence of the debriso-
quin oxidative poor metabolizer phenotype in
American black versus white subjects. Clin Pharma-
col Ther 1991,50:308-13.
114 AMERICAN FAMILY PHYSICIAN
12. Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao
XM, et al. Pronounced differences between native
Chinese and Swedish populations in the polymor-
phic hydroxylations of debrisoquin and S-
mephenytoin. Clin Pharmacol Ther 1992;51:388-
97 (Published erratum appears in Clin Pharmacol
Ther 1994:55:648].
13. Spina E, Ancione M, Di Rosa AE, Meduri M, Caputi
AP Polymorphic debrisoquine oxidation and acute
neuroleptic-induced adverse effects. Eur J Clin
Pharmacol 1992;42:347-8.
14. Cholerton S, Daly AK, Idle JR. The role of individual
human cytochromes P450 in drug metabolism and
clinical response. Trends Pharmacol Sci 1992:13:
434-9.
15. Pollock BG, Mulsant BH, Sweet RA, Rosen J, Altieri
LP, Perel JM. Prospective cytochrome P450 pheno-
typing for neuroleptic treatment in dementia. Psy-
chopharmacol Bull 1995;31:327-31.
16. Yue QY, Svensson JO, Aim C, Sjoqvist F, Sawe J.
Codeine 0-demethylation co-segregates with poly-
morphic debrisoquine hydroxylation. Br J Clin Phar-
macol 1989:28:639-45.
17. Knodell RG, Browne DG, Gwozdz GP, Brian WR,
Guengerich FP Differential inhibition of individual
human liver cytochromes P-450 by cimetidine. Gas-
troenterology 1991; 101:1 680-91.
18. Philip PA, James CA, Rogers HJ. The influence of
cimetidine on debrisoquine 4-hydroxylation in
extensive metabolizers. Eur J Clin Pharmacol
1989:36:319-21.
19. Crewe HK, Lennard MS, Tucker GT Woods FR, Had-
dock RE. The effect of selective serotonin re-uptake
inhibitors on cytochrome P4502D6 (CYP2D6) activ-
ity in human liver microsomes. Br J Clin Pharmacol
1992:34:262-5.
20. Tollefson GD. Adverse drug reactions/interactions
in maintenance therapy J Clin Psych 1993:54
(Suppl):48-60.
21. Shimada T Yamazaki H, Mimura M, Inui Y, Guen-
gerich FP Interindividual variations in human liver
cytochrome P-450 enzymes involved in the oxidation
of drugs, carcinogens and toxic chemicals: studies
vvith liver microsomes of 30 Japanese and 30 Cau-
casians. J Pharmacol Exp Ther.1994:270:414-23.
22. Honig PK, Wortham DC, Zamani K, Conner DP,
Mullin JC, Cantilena LR. Terfenadine-ketoconazole
interaction. Pharmacokinetic and electrocardiograph-
ic consequences. JAMA 1993:269:1513-8 [Published
erratum appears in JAMA 1993:269:2088].
23. Garteiz DA, Hook RH, Walker BJ, Okerholm RA.
Pharmacokinetics and biotransformation studies of
terfenadine in man. Arzneimittel-Forschung 1982;
32:1185-90.
24. Honig PK, Woosley RL, Zamani K, Conner DP, Can-
tilena LR Jr. Changes in the pharmacokinetics and
electrocardiographic pharmacodynamics of terfe-
nadine with concomitant administration of ery-
thromycin. Clin Pharmacol Ther 1992:52:231-8.
25. Haria M, Fitton A, Peters DH. Loratadine. A reappraisal
of its pharmacological properties and therapeutic use
in allergic disorders. Drugs 1994;48:617-37.
VOLUME 57, NUMBER 1 / JANUARY 1,1998
26. von Moltke LL, Greenblatt DJ, Schmider J, Duan SX,
Wright CE, Harmatz JS, et al. Midazolam hydroxy-
lation by human liver microsomes in vitro: inhibition
by fluoxetine, norfluoxetine, and by azole antifun-
gal agents. J Clin Pharmacol 1996:36:783-91.
27. Honig PK, Wortham DC, Hull R, Zamani K, Smith
JE, Cantilena LR. Itraconazoie affects single-dose
terfenadine pharmacokinetics and cardiac repolar-
ization pharmacodynamics. J Clin Pharmacol 1993;
33:1201-6.
28. Honig PK, Wortham DC, Zamani K, Mullin JC, Con-
ner DP, Cantilena LR. The effect of fluconazole on
the steady-state' pharmacokinetics and electrocar-
diographic pharmacodynamics of terfenadine in
humans. Clin Pharmacol Ther 1993:53:630-6.
29. Honig PK, Wortham DC, Zamani K, Cantilena LR.
Comparison of the effect of the macrolide antibi-
otics erythromycin, clarithromycin and azithromycin
on terfenadine steady-state pharmacokinetics and
electrocardiographic parameters. Drug Invest
1994:7:148-56.
30. Solvay's Luvox contraindication against co-adminis-
tration with J&J's Hismanal, MMD's Seldane
prompts FDA review of other SSRI labeling. FDC
Reports: the Pink Sheet 1995:26-9.
31. Ketter TA, Flockhart DA, Post RM, Denicoff K, Paz-
zaglia PJ, Marangell LB, et al. The emerging role of
cytochrome P450 3A in psychopharmacology.
J Clin Psychopharmacol 1995;15:387-98.
32. Marchiando RJ, Cook MD, Jue SG. Probable terfe-
nadine-fluoxetine-associated cardiac toxicity [Let-
ter]. Ann Pharmacother 1995:29:937-8.
33. Swims MP Potential terfenadine-fluoxetine interac-
tion [Letter]. Ann Pharmacother 1993;27:1404-5.
34. Pfizer, Inc. Package insert. Zoloft (sertraline). New
York: 1996.
35. von Moltke LL, Greenblatt DJ, Court MH, Duan SX,
Harmatz JS, Shader Rl. Inhibition of alprazolam and
desipramine hydroxylation in vitro by paroxetine
and fluvoxamine: compar son with other selective
serotonin reuptake inhibitor antidepressants. J Clin
Psychopharmacol 1995:15:125-31.
36. von Moltke LL, Duan SX, Greenblatt DJ, Fogelman
SM, Schmider J, Harmatz JS, et al. Venlafaxine and
metabolites are very weak inhibitors of human
cytochrome P450-3A isoforms. Biol Psychiatry
1997:41:377-80.
37. Wysowski DK, Bacsanyi J. Cisapride and fatal
arrhythmia [Letter]. N EngI J Med 1996:335:290-1.
38. Caley C. Cisapride interaction with antidepressants
[Letter]. Ann Pharmacother 1996:30:684.
39. Cummins LH, Kozak PP Jr, Gillman SA. Ery-
thromycin's effect on theophylline blood level. Pedi-
atrics 1977:59:144.
40. Ruff F, Chu SY, Sonders RC, Senello LT Effect of
multiple doses of clarithromycin on the pharmaco-
kinetics of theophylline [Abstract]. Thirtieth Inter-
science Conference on Antimicrobial Agents and
Chemotherapy. Washington, D.C.: American Soci-
ety for Microbiology,' 1990:761.
41. Hopkins S. Clinical toleration and safety of
azithromycin. Am J Med 1991:91:40S-5S.
JANUARY 1,1998 / VOLUME 57, NUMBER 1
42. Bolt HM, Kappus H, Remmer H. Studies on the
metabolism of ethynylestradiol in vitro and in
vivo: the significance of 2-hydroxylation and the
formation of polar products. Xenobiotica 1973:
3:773-85.
43. Schuetz EG, Wrighton SA, Barwick JL, Guzelian PS.
Induction of cytochrome P-450 by glucocorticoids
in rat liver. I. Evidence that glucocorticoids and
pregnenolone 16 alpha-carbonitrile regulate de
novo synthesis of a common form of cytochrome P-
450 in cultures of adult rat hepatocytes and in the
liver in vivo. J Biol Chem 1984:259:1999-2006.
44. Pelkonen 0, Pasanen M, Kuha H, Gachaiyi B,
Kairaluoma M, Sotaniemi EA, et al. The effect of
cigarette smoking on 7-ethoxyresorufin 0-deethy-
lase and other monooxygenase activities in human
liver: analyses with monoclonal antibodies. BrJ Clin
Pharmacol 1986:22:125-34.
45. Sarkar MA, Jackson BJ. Theophylline N-demethyla-
tions as probes for P4501A1 and P4501A2. Drug
Metab Dispos 1994:22:827-34.
46. Radandt JM, Marchbanks CR, Dudley MN. Interac-
tions of fluoroquinolones with other drugs: mecha-
nisms, variability, clinical significance, and manage-
ment. Clin Infect Dis 1992:14:272-84.
47. Wijnands WJ, Vree TB, van Herwaarden CL. The
influence of quinolone derivatives on theophylline
clearance. BrJ Clin Pharmacol 1986:22:677-83.
48. Sarkar M, Polk RE, Guzelian PS, Hunt C, Karnes HT
in vitro effect of fluoroquinolones on theophylline
metabolism in human liver microsomes. Antimicrob
Agents Chemother 1990:34:594-9.
49. • Parent M, LeBel M.- Meta-analysis of quinolone-
theophylline interactions. Ann Pharmacother 1991:
25:191-4.
50. Raucy JL, Lasker JM, Lieber CS, Black M. Aceta-
minophen activation by human liver cytochromes
P450IIE1 and P450IA2. Arch Biochem Biophys
1989:271:270-83.
51. Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie
BB. Acetaminophen-induced hepatic necrosis. IV.
Protective role of glutathione. J Pharmacol Exp Ther
1973:187:211-7.
52. Loguercio C, Piscopo P Guerriero C, De Girolamo V,
Disalvo D, Del Vecchio Blanco C. Effect of alcohol
abuse and glutathione administration on the circu-
lating levels of glutathione and on antipyrine
metabolism in patients with alcoholic liver cirrhosis.
Scand J Clin Lab Invest 1996:56:441-7.
53. O'Reilly RA. Studies on the optical enantiomorphs
of warfarin in man. Clin Pharmacol Ther 1974:
16:348-54.
54. Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF,
Eddy AC, Aoyama T et al. Hydroxylation of war-
farin by human cDNA-expressed cytochrome
P-450: a role for P-4502C9 in the etiology of (S)-
warfarin-drug interactions. Chem ResToxicol 1992:
5:54-9.
55. Black DJ, Kunze KL, Wienkers LC, Gidal BE, Seaton
TL, McDonnell ND, et al. Warfarin-fluconazole. II.
A metabolically based drug interaction: in vivo
studies. Drug Metab Dispos 1996:24:422-8.
AMERICAN FAMILY PHYSICIAN 115
Cytochrome P450
56. O'Reilly RA. The stereoselective interaction of war-
farin and metronidazole in man. N EngI J Med
1976:295:354-7.
57. O'Reilly RA, Goulart DA, Kunze KL, Neal J, Gibaldi
M, Eddy AC, et al. Mechanisms of the stereoselec-
tive interaction between miconazole and racemic
warfarin in human subjects. Clin Pharmacol Ther
1992:51:656-67.
58. Heimark LD, Wienkers L, Kunze K, Gibaldi M, Eddy
AC, Trager WF, et al. The mechanism of the inter-
action between amiodarone and warfarin in
humans. Clin Pharmacol Ther 1992:51:398-407.
59. Niopas I, Toon S, Rowland M. Further insight into
the stereoselective interaction between warfarin
and cimetidine in man. Br J Clin Pharmacol
1991:32:508-11.
60. Veronese ME, Mackenzie PI, Doecke CJ, McManus
ME, Miners JO, Birkett DJ. Tolbutamide and pheny-
toin hydroxyiations by cDNA-expressed human liver
cytochrome P4502C9. Biochem Biophys Res Com-
mun 1991:175:1112-8 [Published erratum appears
in Biochem Biophys Res Commun 1991:180:1527].
61. Levy RH. Cytochrome P450 isozymes and anti-
epileptic drug interactions. Epiiepsia 1995:36
(Suppl5):S8-13.
62. Bartle WR, Walker SE, Shapero T Dose-dependent
effect of cimetidine on phenytoin kinetics. Clin
Pharmacol Ther 1983:33:649-55.
116 AMERICAN FAMILY PHYSICIAN
63. Wedlund PJ, Aslanian WS, McAllister CB, Wilkinson
GR, Branch RA. Mephenytoin hydroxylation defi-
ciency in Caucasians: frequency of a new oxidative
drug metabolism polymorphism. Clin Pharmacol
Ther 1984:36:773-80.
64. Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz
E, Wilkinson GR,. et al. Interethnic differences in
genetic polymorphism of debrisoquin and
mephenytoin hydroxylation between Japanese and
Caucasian populations. Clin Pharmacol Ther 1985:
38:402-8.
65. Andersson T, Miners JO, Veronese ME, Tassa-
neeyakul W, Meyer UA, Birkett DJ. Identification of
human liver cytochrome P450 isoforms mediating
omeprazole metabolism. Br J Clin Pharmacol
1993:36:521-30.
66. Pearce RE, Rodrigues AD, Goldstein JA, Parkinson
A. Identification of the human P460 enzymes
involved in lansoprazole metabolism. J Pharmacol
Exp Ther 1996:277:805-16.
67. Jung F, Richardson TH, Raucy JL, Johnson EF
Diazepam metabolism by cDNA-expressed human
2C P450s: identification of P4502C18 and
P4502C19 as loyv K(M) diazepam N-demethylases.
Drug Metab Dispos 1997:25:133-9.
68. Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1
protease inhibitors. A review for clinicians. JAMA
1997:277:145-53.
VOLUME 57, NUMBER 1 / JANUARY 1,1998